We have approached oral carcinogenesis by initially searching for evidence of activated tyrosine kinases in naturally occurring human neoplasia, especially squamous cell carcinomas of the head and neck. Initial results have shown that the receptor for epidermal growth factor (EGF) is activated in a number of oral cavity tumors. As a probe for the mechanism of this activation, we have investigated the effect of suramin treatment on EGF receptor activity. It was expected that suramin would greatly reduce the level of intracellular protein-tyrosine phosphorylation by the EGF receptor. Instead, the drug dramatically enhanced protein-tyrosine phosphorylation in epithelial cell tumors. The mechanism at play was shown to involve activation of the growth factor, namely transforming growth factor alpha, that in turn stimulates the tyrosine kinase activity of the EGF receptor. These results suggested that suramin may stimulate the growth of certain tumors, and indeed suramin enhances the growth of oral carcinoma cells in culture. Have also investigated the possible involvement of tyrosine kinases in the development and maintenance of squamous cell carcinomas (SCC) of the upper aerodigestive tract, specifically asking whether aberrant protein- tyrosine phosphorylation could be observed in these tumors. A panel of 19 cell lines established at Wayne State University (WSU) from primary and metastatic SCC of the head and neck were evaluated. Utilizing assays the are capable of scoring EGFR activities, we have found evidence for enhanced EGFR action in 15 of the lines. Futhermore, with respect to normal human keratinocytes each of the 19 cell lines displayed excessive levels of tyrosine phosphorylation of cellular proteins. These results suggest a much broader contribution of the EGFR to naturally occurring carcinogenesis than previously appreciated.